US5668120A - Iontophoretic delivery of bisphosphonates to the alveolar bone - Google Patents
Iontophoretic delivery of bisphosphonates to the alveolar bone Download PDFInfo
- Publication number
- US5668120A US5668120A US08/495,266 US49526695A US5668120A US 5668120 A US5668120 A US 5668120A US 49526695 A US49526695 A US 49526695A US 5668120 A US5668120 A US 5668120A
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- substituted
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- bisphosphonic acid
- hydrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
Definitions
- Certain geminal bisphosphonic acid compounds including their salts and esters, are effective against alveolar bone loss and unwanted tooth movement. Problems with such compounds include that the compounds are generally negatively charged molecules and not capable of penetrating oral tissue very readily. Although such drugs have been administered systemically, their rate of absorption is quite poor.
- Iontophoresis is a technique for delivering ions into a person's tissue by placing a solution, or other medium containing the ion, in contact or close proximity with the tissue; the solution or medium containing the ions is typically carried by a first electrode pouch or receptacle. A second or dispersive electrode is placed against the tissue within some proximity of the first electrode. Ions are caused to migrate from the ion-carrying medium through the tissue by the application of an electrical potential or voltage of the appropriate polarity to the two electrodes. A controlled current is established by providing a sufficient voltage differential between the first and second electrodes, and placing a limiting resistance or other current-limiting device elsewhere in the circuit.
- the present invention relates to methods of inhibiting alveolar bone resorption or the undesirable movement of teeth of a human or other animal comprising:
- n is an integer from 0 to 7 (preferably from 0 to 3, more preferably 1);
- R 1 is hydrogen, chloro, amino, or hydroxy (preferably hydrogen or hydroxy);
- X is --NH--, quaternary amine, oxygen, sulfur, or a single bond (preferably --NH-- or single bond);
- R 2 is a 5- to 7-membered carbocycle (preferably 6- to 7- membered, more preferably benzene or cycloheptyl), a 5- to 7-membered heterocycle having from 1 to 3 heteroatoms (preferably a 6-membered heterocycle having 1 or 2 nitrogen atoms, wherein a ring nitrogen may be quaternar
- This invention relates to iontophoretic delivery to the oral tissue of a safe and effective amount of geminal bisphosphonic acid compounds ("BPs”), or their pharmaceutically-acceptable salts and esters.
- BPs geminal bisphosphonic acid compounds
- n is an integer from 0 to 7 (preferably from 0 to 3, more preferably 1);
- R 1 is hydrogen, chloro, amino, or hydroxy (preferably hydrogen or hydroxy);
- X is --NH--, quaternary amine, oxygen, sulfur, or a single bond (preferably --NH-- or single bond);
- R 2 and is a subsituted or unsubstituted 5- to 7-membered carbocycle (preferably 6- to 7- membered, more preferably benzene or cycloheptyl), a subsituted or unsubstituted 5- to 7-membered heterocycle having from 1 to 3 heteroatoms (preferably a 6-membered heterocycle having 1 or 2 nitrogen atoms, wherein a ring nitrogen may be quaternarized), --NH 2 , amino substituted with one alkyl or two alkyl (preferably C 1 -C 5 ) groups to give a secondary or ter
- pharmaceutically-acceptable salts and esters means hydrolyzable esters and salts of the bone-active phosphonates which have the same general pharmacological properties as the acid form from which they are derived, and which are pharmaceutically acceptable.
- Pharmaceutically-acceptable salts include, for example, alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium and magnesium), non-toxic heavy metals (e.g., stannous and indium), and ammonium and low molecular weight substituted ammonium (e.g., mono-, di- and triethanolamine) salts.
- alkali metals e.g., sodium and potassium
- alkaline earth metals e.g., calcium and magnesium
- non-toxic heavy metals e.g., stannous and indium
- ammonium and low molecular weight substituted ammonium e.g., mono-, di- and triethanolamine
- esters include unsubstituted and substituted alkyl, aryl and phosphoryl esters.
- Nonlimiting examples of pharmaceutically-acceptable esters include, for example, isopropyl, tertiarybutyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifiuoroethyl, p-toluenesulfonylethyl, glycyl, sarcosyl, benzyl, phenyl, 1,2-hexanoylglyceryl, p-nitrophenyl, 2,2 dimethyl-1,3-dioxolene-4-methyl, isopentenyl, o-carbomethoxyphenyl, piraloyloxymethylsalicylyl, diethylamidophosphoryl, pivaloyloxymethyl, acyloxymethyl, propionyloxymethyl, isobutyryloxymethyl, dodecyl, o
- Preferred bone-active phosphonates useful in the methods of this invention include: referred bone-active phosphonates useful in the methods of this invention include: 1-hydroxyethane-1,1-bisphosphonic acid; dichloromethane bisphosphonic acid; 3-amino-1-hydroxypropane-1,1-bisphosphonic acid; 6-amino-1-hydroxyhexane-1,1-bisphosphonic acid; 4-amino-1-hydroxybutane-1,1-bisphosphonic acid; 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonic acid; 2-(N-imidazoyl)-1-hydroxyethane-1,1-bisphosphonic acid; 3-(N-pentyI-N-methylamino)-1-hydroxypropane-1,1-bisphosphonic acid; 3-(N-pyrollidino)-1-hydroxypropane-1,1-bisphosphonic acid; N-cycloheptylaminomethanebisphosphonic acid; S-(p-chlorophenyl) thi
- bone-active phosphonates useful in the methods of this invention include: 4-amino-1-hydroxybutane-1,1-bisphosphonic acid; 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonic acid; 3-(N-pentyl-N-methylamino)-1-hydroxypropane-1,1-bisphosphonic acid; N-cycloheptylaminomethanebisphosphonic acid; S-(p-chlorophenyl) thiomethane-bisphosphonic acid; (7-dihydro-1-pyrindine)methane bisphosphonic acid; and pharmaceutically-acceptable salts and esters thereof.
- aminoethane bisphosphonic acid compounds are best prepared as follows:
- risedronate denotes the bisphosphonate compound 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid and has the following structure: ##STR4##
- risedronate active ingredient includes risedronate, risedronate salts, and risedronate esters, or any mixture thereof. Any pharmaceutically-acceptable, non-toxic salt or ester of risedronate may be used as the risedronate active ingredient in the oral dosage forms useful for the present invention.
- the salts of risedronate may be acid addition salts, in particular the hydrochloride, but any pharmaceutically-acceptable, non-toxic organic or inorganic acid salt may be used.
- salts formed with the carboxylic acid group may be used, including, but not limited to, alkali metal salts (K, Na) and alkaline earth metal salts (Ca, Mg), the Ca- and Na- salts being preferred.
- esters of risedronate which are suitable for use as the active ingredient in the invention disclosed herein are straight chain or branched chain C 1 -C 18 alkyl esters, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl; straight chain or branched C 2 -C 18 alkenyl esters, including, but not limited to, vinyl, alkyl, undecenyl, and linolenyl; C 3 -C 8 cycloalkyl esters, including, but not limited to, vinyl, alkyl, undecenyl, and linolenyl; C 3 -C 8 cycloalkyl esters, including, but not limited to, cyclopropyl,
- risedronate active ingredient depends on the selected type of formulation.
- the physical and chemical characteristics of the active ingredient must be taken into account when selecting suitable pharmaceutically-acceptable excipients for use in the dosage forms containing the risedronate active ingredient.
- the above-named compound is prepared via a typical Michael reaction between tetraethyl vinylbisphosphonate and 2-amino-3-picoline. (See H. O. House, Modern Synthetic Reaction 2nd Ed. W. A. Benjamin Inc. p. 595-623, the disclosure of which is incorporated herein by reference.)
- N-(2-pyridyl)-2-aminoethane BP and N-(2-(5-picolyl))-2-aminoethane BP are prepared in an identical manner.
- a 3-neck round-bottom flask fitted with a reflux condenser and a magnetic stir bar is charged with 6.94 grams (0.04 mole) 2-pyridine acetic acid, 9.84 grams (0.14 mole) phosphorus acid, and 150 ml of chlorobenzene.
- This reaction mixture is heated on a boiling water bath, and 16.5 grams (0.12 mole) phosphorus trichloride is added dropwise with stirring.
- This reaction mixture is heated for 21/2hours during which time a viscous yellow oil forms.
- the reaction mixture is then cooled in an ice bath and the chlorobenzene solution is decanted off from the solidified product.
- the reaction flask containing this solidified product is charged with 150 ml of water and heated in a boiling water bath for several hours.
- the hot solution is then filtered through Celite 545®. 300 ml of methanol is added to the warm filtrate solution, and precipitate develops. After cooling in ice for 1 hour, the precipitate is filtered off and then washed with methanol/water (1/1 volume/volume), methanol, and ether, and air dried. The product may be recrystallised from hot water.
- the sample is characterized by P-31 and C-13 NMR.
- the effective amount of active agent means that amount needed to produce the intended result following its iontophoretic administration.
- the effective amount will vary, depending, among other factors, on the physiological effect as determined by the tissue level of desired active agent, rate of clearance of active agent, and intradermal metabolism desired.
- the amount of active agent per administration and incorporated into a carrier for iontophoretic delivery should be from about 0.002 mg to about 20 mg preferably from about 0.01 mg to about 10 mg more preferably from about 0.1 mg to about 5 mg of the active agent.
- safe and effective amount as used herein is meant an amount of current sufficient to induce a significant positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
- the safe and effective amount of the current may vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors.
- High voltage electroporation as described in U.S. Pat No. 5,019,034, issued May 28, 1991 to Weaver et. al, and incorporated herein by reference may also be used.
- compositions of the present invention are particularly advantageous compared to prior methods and compositions.
- Prior methods and compositions typically relied on tissue damaging or tissue altering compositions such as permeation enhancers.
- tissue permeation enhancers that alter the gingival epithelium
- the compositions and methods of the present invention are not directed toward altering the gingival epithelium and yet achieve an enhanced tissue concentration with iontophoretic delivered active agents.
- Ion refers to an atom or radical that has lost or gained one or more electrons to acquire an electric charge.
- active agent refers to the entity chosen to be delivered by iontophoresis. Thus, active agent refers to the chosen entity and the ionic form of the chosen entity for delivery, such as halide salts of a chosen entity to be delivered (e.g., risedronate and an ionic form of risedronate for delivery such as calcium risedronate).
- Patient refers to animals, including humans, household animals such as dogs and cats, livestock such as cattle, horses, sheep, pigs, goats and rabbits, laboratory animals such as mice and rats, and zoo animals such as exotic species.
- iontophoretic devices comprise at least two electrodes, an electrical energy source (e.g., a battery) and at least one reservoir which contains an active agent to be delivered.
- an electrical energy source e.g., a battery
- iontophoretic devices are known, such as those disclosed in P. Tyle, Pharmaceutical Research 3:318 (1986).
- the active agent must be maintained in the donor compartment in a chemically pure form. Electrochemical reaction of the active at the electrode are to be avoided.
- iontophoresis of an active agent the compound passes through the gingival epithelium, through the intervening oral tissue and into the alveolar bone. In a situation wherein the gingival epithelium is the rate-limiting barrier, the blood flow in the vasculature is of little consequence.
- rate of delivery of the active agent is enhanced over passive delivery, as in the case of iontophoresis, to the point where the ability of the vasculature to remove the compound is rate-limiting, then the blood flow in the vasculature becomes significant. Iontophoresis of a vasoconstrictor with an active agent, therefore enhances the tissue concentration of iontophoretically delivered active agents.
- the ability to maintain proper concentration ratios of active agent to vasoconstrictor will depend upon the iontophoretic properties of the active agent and vasoconstrictor, and hence the relative proportions of the vasoconstrictor combined with the active agent.
- compositions refers to the addition of salts, mold complexes, solid and liquid carriers, ionic forms, and the like, which do not significantly or adversely affect the properties of the active agent or its stability to be iontophoretically delivered.
- Pharmaceutically-acceptable compositions can be prepared by reference to general texts in the field, such as Remington's Pharmaceutical Sciences, Ed. A. F. Gennaro, 17th ed., 1985, Mack Publishing Co., Easton, Pa.
- the pharmaceutically-acceptable composition, or reservoir, that contains the active agent to be delivered can be in the form of any material suitable for making contact between the iontophoresis unit and the oral tissue. Suitable materials include, but are not limited to, solutions, foams, gels, creams, and lotions; nonionic gel is preferred.
- Iontophoresis solutions can comprise a liquid vehicle such as water, alcohol, propylene glycol, polyethylene glycol, or a mixture thereof.
- a liquid vehicle such as water, alcohol, propylene glycol, polyethylene glycol, or a mixture thereof.
- Such a vehicle may comprise from about 70% to about 99%, preferably from about 80% to about 98% of the solution.
- agents may be added.
- agents can include surface active agents, such as poloxamer, sodium lauryl sulfate, and like; preservatives, such as methyl paraben, cetyl pyridinum chloride; flavoring agents, and coloring agents.
- Iontophoresis gels can comprise a liquid or solution composition such as that described above, gelled with a suitable gelling agent.
- suitable gelling agents may include hydroxy propyl methyl cellulose, carboxy vinyl copolymer (Carbopol), food starch such as corn starch and potato starch, gums such as xanthan, karaya, alginic acid, biopolymers like chitosan, other polysaccharide gels, or similar hydrophilic aqueous gels capable of carrying ions.
- gels include polyvinyl alcohol, polymethyl pyrrolidine, polyvinyl pyrrolidone, methyl cellulose, polyacrylamide, polyhemas, polyhema derivatives, food starch such as corn and potato starches and the like.
- the matrix selected should be nonirritating to a person's tissue, the matrix should have suitable viscosity and surfactant properties to obtain good electrical contact with the tissue, and the ability to act as a carrier medium for the bisphosphonate ions.
- the preferred matrix is starch.
- a gelling agent may constitute from about 0.1% to about 10% of the composition, preferably between 0.2 to 2%.
- Optional components may be added.
- Such optional components can include preservative such as methyl paraben, flavors, and sweeteners such as sorbitol. For example, if higher amount alcohol is used as a vehicle, additional preservative may not be necessary.
- an anhydrous gel can also be formulated, for example, by using propylene glycol as a vehicle, without any water, and gelling propylene glycol with a suitable cellulosic or other polymer.
- Iontophoresis foaming paste can comprise a pharmaceutically acceptable foaming surface active agent such as sodium lauryl sulfate, is sodium dodecyl sulfate, poloxamer, and like.
- a pharmaceutically acceptable foaming surface active agent such as sodium lauryl sulfate
- sodium dodecyl sulfate sodium dodecyl sulfate, poloxamer, and like.
- sodium lauryl sulfate sodium dodecyl sulfate, poloxamer, and like.
- sodium lauryl sulfate sodium dodecyl sulfate, poloxamer, and like.
- sodium lauryl sulfate sodium dodecyl sulfate
- poloxamer poloxamer
- a pharmaceutically-acceptable dental abrasive is added. Suitable dental abrasives include colloidal silicon dioxide and others such as those disclosed by Cooley et al. in U.S.
- an opacifier such as titanium dioxide can be added to make the formulation opaque. In its absence, the composition would be clear or translucent.
- Iontophoresis lotions and creams can comprise a fatty or oily component, an aqueous component, and a surface active agent as an emulsifier.
- Suitable fatty components can include petrolatum, fatty alcohol, fatty acid, and the like.
- Suitable surface active agents may include sodium lauryl sulfate, sorbitan esters, polyoxyethylene and polyoxypropylene derivatives and copolymers, natural and synthetic gums, cellulosics, and like.
- the making of a suitable lotion or cream for use in this invention is well known to those familiar with the science and art of making emulsion products.
- the pH must be maintained in a range that is physiologically acceptable and maintains the bisphosphonate in a negatively charged state, preferably from about pH 3 to about pH 9, more preferably from about 5 to about 8. For short duration treatments (e.g., 2-3 minutes), a wider range might be tolerated.
- a key to maintaining constant pH over a longer period e.g. longer than about 5 minutes is the use of non-polarizing electrodes rather than metal electrodes or a combination of a salt bridge and a large surfaced metal electrode.
- non-polarizing electrodes include Ag/AgCl, and calomel electrodes.
- Ion exchange membranes which separate the donor solution from the anode or cathode may also be employed for this purpose, especially for oxidatively sensitive actives.
- compositions useful for purposes of this invention have a maximum osmolarity of less than or equal to about 150 mM; preferably the osmolarity is less than this amount.
- the maximum ionic concentration should be a maximum of about 150 mM, preferably less.
- the active agent ions comprise a minimum of 25% of the mobile ion concentration of such compositions.
- the active agent for use in the method of the invention can be delivered alone, or in combination with other substances.
- Other substances can include other permeation enhancers, buffers, bacteriostatics, stabilizers, antioxidants, other active agents and the like, anti-inflammatories, antihistamines, antibiotics.
- the active agent is for non-systemic delivery.
- antibiotics include clindamycin, streptomycin, vancomycin, tetracyclines, metronidazole and azithromycin.
- the composition is typically dissolved in a suitable carrier for iontophoretic delivery.
- ethanol may increase skin permeability and enhance bisphosphonate delivery.
- Perfumes and/or flavoring agents could be added, especially if the treatment were to be applied in the oral cavity without a patch.
- a local anesthetic e.g. lidocaine, benzocaine
- a composition comprising a local anesthetic should be applied to the gingival tissue and left for at least approximately 30 seconds before the iontophoretic current is applied.
- Additional optional ingredients include anti-inflammatory agents to relieve pain and inflammation.
- Anionic NSAIDs are preferred, including but not limited to, ⁇ -propionic acids (e.g. ibuprofen, ketoprofen, naproxen, flurbiprofen), ketorolac, indomethacin, and meclofenamic acid.
- compositions previously described can be applied directly to the oral tissue or in a patch. In the former case, the application site must subsequently be contacted with an electrode to initiate iontophoretic treatment. All dose forms must be electrically conductive. Preferred dose forms include conductive gels applied with or without a patch, and conductive solutions contained within a patch.
- Iontophoretic treatment according to this invention can last for from about 1 minute to about 24 hours, preferably for from about 2 minutes to about 2 hours, more preferably for from about 3 minutes to about 30 minutes, more preferably still from about 5 minutes to about 10 minutes.
- the frequency of treatment should be from about once per three months to about 10 times per day, preferably from about once per week to about 4 times per day, more preferably from about one time per day to about 2 times per day.
- Preferably a minimum of two treatments are administered.
- the treatment regimen for use in the present invention includes the consideration of a variety of factors, including the type, age, weight, sex, medical condition of the patient, severity of the condition and active agent to be delivered.
- An ordinarily skilled dentist or physician can readily determine and prescribe and administer the effective amount of the agent required to prevent or arrest the progress of the condition by employing relatively low doses at first and subsequently increase the dose until a maximum response is obtained.
- the solution comprising 50 mM risedronate is applied to the gingival margin of a periodontitis patient with progressive disease.
- An iontophoretic current of 0.2 milliamperes is applied for 10 minutes.
- the treatment is repeated one week later.
- the progression of alveolar bone resorption is arrested for three months as determined by radiographic evaluation.
- the gel can be formulated using techniques well known in the oral care field.
- the gel comprising 20 mM of EHDP is applied into the periodontal pockets of a periodontitis patient and 0.5 milliamperes of iontophoretic current are applied for ten minutes on each of four occasions over a one month period. Subsequent clinical and radiological evaluation demonstrate that the progression of alveolar bone loss has been arrested.
- the gel can be formulated using techniques well known in the oral care field.
- An animal having experimentally induced periodontitis is treated on a first day by application of 50 ⁇ l of the gel comprising 8 mM risedronate around the neck of the tooth nearest a site of alveolar bone resorption.
- a current of 0.1 mA is applied to the gel for 10 min.
- the treatment is repeated on the third day again on the fifth day.
- loss of bone mineral density is found to be prevented relative to an untreated control site in the animal's mouth.
- the lotion can be formulated using techniques well known in the oral care field.
- the lotion comprising 80 mM of alendronate is applied to the gingival margin of that tooth and an iontophoretic current of 1 milliampere is applied for five minutes on two occasions, three weeks apart. Subsequent clinical evaluation demonstrates that the tooth is stable and there is no indication of tooth movement back toward its prior position.
- the paste can be formulated using techniques well known in the oral care field.
- the anchor teeth of a patient are treated every other month by application to the gingival margin of the foaming paste comprising 10 mM risedronate in conjunction with 15 minutes of a 0.1 milliamperes iontophoretic current.
- This treatment leads to stable re-positioning of the desired teeth within 12 months without changing the position or stability of the anchor teeth.
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US08/495,266 US5668120A (en) | 1994-04-18 | 1995-06-27 | Iontophoretic delivery of bisphosphonates to the alveolar bone |
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US22898294A | 1994-04-18 | 1994-04-18 | |
US08/495,266 US5668120A (en) | 1994-04-18 | 1995-06-27 | Iontophoretic delivery of bisphosphonates to the alveolar bone |
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US22898294A Continuation | 1994-04-18 | 1994-04-18 |
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US08/495,266 Expired - Fee Related US5668120A (en) | 1994-04-18 | 1995-06-27 | Iontophoretic delivery of bisphosphonates to the alveolar bone |
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US (1) | US5668120A (fr) |
JP (1) | JPH09511927A (fr) |
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US5958908A (en) * | 1994-09-21 | 1999-09-28 | Merck & Co., Inc. | Sodium alendronate preparation for local administration |
US5990098A (en) * | 1995-07-10 | 1999-11-23 | Gador, S.A. | Therapeutic use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid and its salts |
US5998390A (en) * | 1998-09-28 | 1999-12-07 | The Research Foundation Of State University Of New York | Combination of bisphosphonate and tetracycline |
US6008206A (en) * | 1994-09-21 | 1999-12-28 | Merck & Co., Inc. | Sodium alendronate preparation for local administration |
WO2000025858A1 (fr) | 1998-11-02 | 2000-05-11 | Alza Corporation | Dispositif d'electrotransport comprenant un agent antimicrobien compatible |
US6117856A (en) * | 1996-02-14 | 2000-09-12 | Binderman; Itzhak | Topical bisphosphonates for prevention of bone resorption |
WO2002081024A1 (fr) | 2001-04-04 | 2002-10-17 | Alza Corporation | Dispositif d'administration transdermique par electrotransport comprenant une composition de reservoir compatible antimicrobienne |
US6602296B1 (en) * | 1997-09-09 | 2003-08-05 | The University Of Western Australia | Chemical supplementation of bone |
US6630453B1 (en) | 1999-05-04 | 2003-10-07 | Strakan Limited | Androgen derivatives and uses thereof |
US20040131687A1 (en) * | 2002-10-04 | 2004-07-08 | Kraft Edward R. | Photokinetic delivery of biologically active substances using pulsed incoherent light |
US20050015155A1 (en) * | 1997-09-09 | 2005-01-20 | Day Robert Edward | Chemical supplementation of bone |
US20050220439A1 (en) * | 2004-03-19 | 2005-10-06 | Carton Owen A | Interactive multimedia system and method |
Families Citing this family (9)
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EP0824341A4 (fr) * | 1995-05-12 | 1999-07-07 | Merck & Co Inc | Prevention des pertes de dnets par l'administration d'alendronate ou de ses sels |
US5735810A (en) * | 1996-06-14 | 1998-04-07 | Becton Dickinson And Company | Device for the iontophoretic administration of bisphosphonates |
US5730715A (en) * | 1996-06-14 | 1998-03-24 | Becton Dickinson And Company | Method for the iontophoretic administration of bisphosphonates |
US6214834B1 (en) | 1997-03-28 | 2001-04-10 | Dupont Pharmaceuticals Company | Integrin inhibitor prodrugs |
US6015801A (en) * | 1997-07-22 | 2000-01-18 | Merck & Co., Inc. | Method for inhibiting bone resorption |
US5994329A (en) * | 1997-07-22 | 1999-11-30 | Merck & Co., Inc. | Method for inhibiting bone resorption |
US6432932B1 (en) | 1997-07-22 | 2002-08-13 | Merck & Co., Inc. | Method for inhibiting bone resorption |
GB2336311A (en) * | 1998-04-15 | 1999-10-20 | Merck & Co Inc | Bisphosphonate Dosing Regimen |
US6331533B1 (en) * | 1998-11-16 | 2001-12-18 | Merck & Co., Inc. | Method for inhibiting dental resorptive lesions |
Citations (7)
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- 1995-03-24 WO PCT/US1995/003727 patent/WO1995028145A1/fr active Application Filing
- 1995-03-24 JP JP7526974A patent/JPH09511927A/ja active Pending
- 1995-06-27 US US08/495,266 patent/US5668120A/en not_active Expired - Fee Related
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US6008206A (en) * | 1994-09-21 | 1999-12-28 | Merck & Co., Inc. | Sodium alendronate preparation for local administration |
US5958908A (en) * | 1994-09-21 | 1999-09-28 | Merck & Co., Inc. | Sodium alendronate preparation for local administration |
US5990098A (en) * | 1995-07-10 | 1999-11-23 | Gador, S.A. | Therapeutic use of 1-amino-3-(N,N-dimethylamino)-propylidene-1,1-bisphosphonic acid and its salts |
US6117856A (en) * | 1996-02-14 | 2000-09-12 | Binderman; Itzhak | Topical bisphosphonates for prevention of bone resorption |
US6602296B1 (en) * | 1997-09-09 | 2003-08-05 | The University Of Western Australia | Chemical supplementation of bone |
US20050015155A1 (en) * | 1997-09-09 | 2005-01-20 | Day Robert Edward | Chemical supplementation of bone |
US5998390A (en) * | 1998-09-28 | 1999-12-07 | The Research Foundation Of State University Of New York | Combination of bisphosphonate and tetracycline |
US6114316A (en) * | 1998-09-28 | 2000-09-05 | Research Foundation Of S.U.N.Y. | Combination of bisphosphonate and tetracycline |
AU766913B2 (en) * | 1998-11-02 | 2003-10-23 | Alza Corporation | Electrotransport device including a compatible antimicrobial agent |
US6181963B1 (en) | 1998-11-02 | 2001-01-30 | Alza Corporation | Transdermal electrotransport delivery device including a cathodic reservoir containing a compatible antimicrobial agent |
WO2000025858A1 (fr) | 1998-11-02 | 2000-05-11 | Alza Corporation | Dispositif d'electrotransport comprenant un agent antimicrobien compatible |
KR100649380B1 (ko) * | 1998-11-02 | 2006-11-24 | 알자 코포레이션 | 융화성 항균제를 포함하는 전기수송 장치 |
US6630453B1 (en) | 1999-05-04 | 2003-10-07 | Strakan Limited | Androgen derivatives and uses thereof |
US7761147B2 (en) | 2001-04-04 | 2010-07-20 | Alza Corporation | Transdermal electrotransport delivery device including an antimicrobial compatible reservoir composition |
WO2002081024A1 (fr) | 2001-04-04 | 2002-10-17 | Alza Corporation | Dispositif d'administration transdermique par electrotransport comprenant une composition de reservoir compatible antimicrobienne |
US20020198484A1 (en) * | 2001-04-04 | 2002-12-26 | Young Wendy A. | Transdermal electrotransport delivery device including an antimicrobial compatible reservoir composition |
US20050187511A1 (en) * | 2001-04-04 | 2005-08-25 | Young Wendy A. | Transdermal electrotransport delivery device including an antimicrobial compatible reservoir composition |
US7801599B2 (en) | 2001-04-04 | 2010-09-21 | Alza Corporation | Transdermal electrotransport delivery device including an antimicrobial compatible reservoir composition |
US7054682B2 (en) | 2001-04-04 | 2006-05-30 | Alza Corp | Transdermal electrotransport delivery device including an antimicrobial compatible reservoir composition |
US20070100274A1 (en) * | 2001-04-04 | 2007-05-03 | Young Wendy A | Transdermal Electrotransport Delivery Device Including An Antimicrobial Compatible Reservoir Composition |
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US20040131687A1 (en) * | 2002-10-04 | 2004-07-08 | Kraft Edward R. | Photokinetic delivery of biologically active substances using pulsed incoherent light |
US20090156463A1 (en) * | 2002-10-04 | 2009-06-18 | Photokinetix, Inc. | Photokinetic delivery of biologically active substances using pulsed incoherent light |
US7458982B2 (en) | 2002-10-04 | 2008-12-02 | Photokinetix, Inc. | Photokinetic delivery of biologically active substances using pulsed incoherent light |
US7854753B2 (en) | 2002-10-04 | 2010-12-21 | Photokinetix, Inc. | Photokinetic delivery of biologically active substances using pulsed incoherent light |
US20050220439A1 (en) * | 2004-03-19 | 2005-10-06 | Carton Owen A | Interactive multimedia system and method |
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JPH09511927A (ja) | 1997-12-02 |
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